The United States government has certain rights in this invention by virtue of National Institutes of Health grant number RO1NS33325 to Bruce A. Yankner.
Alzheimer""s disease (AD) is the most common cause of dementia in the aged population. The accumulation of large numbers of senile plaques containing the 40-42 amino acid amyloid xcex2 protein (Axcex2) is a classic pathological feature of AD. Both genetic and cell biological findings suggest that the accumulation of Axcex2 in the brain is the likely cause of AD (Yankner, B. A. (1996) Neuron 16, 921-932.; Selkoe, D. J. Science 275, 630-631 (1997)). Strong genetic evidence in support of the pathogenic role of Axcex2 came from the observation that individuals who inherit mutations in the amyloid precursor protein almost invariably develop AD at an early age. These mutations increase the production of a long variant of the Axcex2 peptide that forms senile plaques in the brain (Goate et al., (1991) Nature 349, 704-706). Mutations and allelic variations in other genes that cause AD, including the presenilins and apolipoprotein E, also result in increased production or deposition of the Axcex2 peptide. Reiman, et al. (1996) N.E.J.Med. 334, 752-758, reported that in middle age, early to mid 50""s, individuals who are homozygous for the Apo E4 gene have reduced glucose metabolism in the same regions of the brain as in patients with Alzheimer""s disease. These findings suggest that the pathological changes in the brain associated with this gene start early. Furthermore, individuals with Down""s syndrome overexpress the amyloid precursor protein, develop Axcex2 deposits in the brain at an early age, and develop Alzheimer""s disease at an early age. Finally, the Axcex2 protein has been demonstrated to be highly toxic to nerve cells. Thus, it is widely believed that drugs which decrease the levels of Axcex2 in the brain would prevent Alzheimer""s disease.
The known genetic causes of AD can account for only a small proportion of the total number of cases of AD. Most cases of AD are sporadic and occur in the aged population. A major goal of research is the identification of environmental factors that predispose to AD that would be amenable to therapeutic measures.
It is therefore an object of the present invention to provide methods for predicting populations at risk of developing AD.
It is another object of the present invention to provide diagnostics and pharmaceuticals to decrease the production of amyloid xcex2 protein (Axcex2), and thereby to prevent or reduce the liklihood of developing AD.
It is a further object of the present invention to provide pharmaceutical treatments to treat AD in patients having the neuropsychiatric or diagnostic criteria for AD.
Blood cholesterol levels are correlated with production of amyloid xcex2 protein (Axcex2), and are predictors of populations at risk of developing AD. Methods for lowering blood cholesterol levels cain be used to decrease production of Axcex2, thereby decreasing the risk of developing AD. The same methods and compositions can also be used for treating individuals diagnosed with AD. Methods include administration of compounds which increase uptake of cholesterol by the liver, such as the administration of HMG CoA reductase inhibitors, administration of compounds which block endogenous cholesterol production, such as administration of HMG CoA reductase inhibitors, administration of compositions which prevent uptake of dietary cholesterol, and administration of combinations of any of these which are effective to lower blood cholesterol levels. Methods have also been developed to predict populations at risk, based on the role of cholesterol in production of Axcex2. For example, individuals with Apo E4 and high cholesterol, defined as a blood cholesterol level of greater than 200 mg/dl, post menopausal women with high cholesterol levelsxe2x80x94especially those who are not taking estrogen, or individuals which high blood cholesterol levels who are not obese are all at risk of developing AD if blood cholesterol levels are not decreased. In the preferred embodiment, individuals with these risk factors are treated to lower blood cholesterol levels prior to developing any mental impairment attributable to AD, based on accepted neuropsychiatric and diagnostic criteria in clinical practice. Treatment is based on administration of one or more compositions effective to lower cholesterol blood levels at least 10%, which is believed to be sufficient to decrease production of Axcex2.
Diagnostic kits based on the discovery of these risk factors include reagents for measurement of cholesterol, total lipoproteins, and/or Apo E4.
The examples demonstrate the use of HMG CoA reductase inhibitors to treat Alzheimer""s disease. Rats fed a high cholesterol diet show increased levels of the Alzheimer""s disease Axcex2 protein in the brain. Cholesterol has been shown to increase the amount of Axcex2 in human neurons in culture. The HMG CoA reductase inhibitors reduce cholesterol production. Several different HMG CoA reductase inhibitors, including lovastatin, simvastatin, fluvastatin, pravastatin and compactin, significantly inhibit the level of Axcex2 production in human neuronal cultures.
Individuals at increased risk for Axcex2 accumulation and Alzheimer""s disease are those who carry a copy of the apolipoprotein E4 gene (Strittmatter et al., (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 1977-1981), those with trisomy 21 (Down""s syndrome) (Mann and Esiri, (1989) J. Neurol. Sci. 89, 169-179)), and individuals who carry a mutation in one of the genes that encode the amyloid precursor protein, presenilin-1 or presenilin-2 (reviewed in Yankner, 1996). In addition, individuals with a family history of Alzheimer""s disease have been documented to be at increased risk of Alzheimer""s disease (Farrer et al., (1989) Ann. Neurol. 25, 485-492; van Duijn et al., (1991) Int. J. Epidemiol. 20 (suppl 2). S13-S20), and could therefore benefit from prophylactic treatment with an HMG CoA reductase inhibitor.
Methods have also been developed to predict populations at risk, based on the role of cholesterol in production of Axcex2. Several risk factors for developing AD have been identified. These include:
(1) individuals with Apo E4 and high cholesterol, defined as a blood cholesterol level of greater than 200 mg/dl,
(2) post menopausal women with high cholesterol, especially those who are not taking estrogen,
(3) young individuals with high blood cholesterol levels who are not obese (age 48-65 yrs),
(4) individuals with high blood cholesterol levels who have a family history of AD,
(5) individuals with high blood cholesterol levels who have a family history of AD, and
(6) all adult individuals with Down""s syndrome.
These individuals are all at risk of developing AD if blood cholesterol levels are not decreased. In the preferred embodiment, individuals with these risk factors are treated to lower blood cholesterol levels prior to developing any mental impairment attributable to AD using accepted neuropsychiatric and diagnostic criteria for probable Alzheimer""s disease (McKhahn et al. (1984) Neurology 34:939-944).
Individuals can be screened using standard blood tests for cholesterol, ApoE4, and/or total lipoprotein levels, as well as by taking a medical and family history. In addition, over the counter immunoassay tests can be used by individuals who may be at risk, so that they can seek further medical advise. These immunoassay kits can be qualitative and/or quantitative for elevated cholesterol, total lipoproteins, and Apo E4.
Methods for lowering blood cholesterol levels can be used to decrease production of Axcex2, thereby decreasing the risk of developing AD. The same methods can also be used to treat patients who have already been diagnosed with AD. Methods include administration of compounds which increase uptake of cholesterol by the liver, such as the administration of HMG CoA reductase inhibitors, administration of compounds which. block endogenous cholesterol production, such as administration of HMG CoA reductase inhibitors, administration of compositions which prevent uptake of dietary cholesterol, and administration of combinations of any of these which are effective to lower blood cholesterol levels.
The examples indicate that several different HMG CoA reductase inhibitors reduce the production of Axcex2. HMG CoA reductase inhibitors may act to lower cholesterol at several different levels. For example, HMG CoA reductase inhibitors have been shown to lower blood cholesterol levels by upregulating lipoprotein clearance receptors in the liver (Brown and Goldstein, (1986) Science 232, 3447). In addition, HMG CoA reductase inhibitors will directly inhibit cholesterol synthesis in neurons. Since every HMG CoA reductase inhibitor tested reduces Axcex2 production, it is anticipated that new members of this class of drugs will also inhibit Axcex2 production. Furthermore, since increased dietary cholesterol increases Axcex2 in the brain, drugs which act through other mechanisms to reduce cholesterol will also inhibit Axcex2 production.
Representative CoA reductase inhibitors include the statins, including lovastatin, simvastatin, compactin, fluvastatin, atorvastatin, cerivastatin, and pravastin. These are typically administered orally.
Compounds which inhibit cholesterol biosynthetic enzymes, including 2,3-oxidosqualene cyclase. squalene synthase, and 7-dehydrocholesterol reductase, can also be used.
Representative compositions which decrease uptake of dietary cholesterol include the bile acid binding resins (cholestryramine and colestipol) and the fibrates (clofibrate). Probucol, nicotinic acid, garlic and garlic derivatives, and psyllium are also used to lower blood cholesterol levels. Probucol and the fibrates increase the metabolism of cholesterol-containing lipoproteins. The cholesterol-lowering mechanism of nicotinic acid is not understood.
Although the preferential route of administration of HMG CoA reductase inhibitors would be oral, the drugs could also by administered by intravenous, subcutaneous or intramuscular routes. In some cases, direct administration into the cerebrospinal fluid may be efficacious.